Progress has been rapid in HER2+ breast cancer treatment, which I think largely reflects the understanding that HER2 is a key disease driver and a target that often remains valid through multiple lines of therapy. That realization has led to the development of a number of different HER2-targeted therapies, which has been the major advancement. We have gone from having no drugs for HER2+ breast cancer, to first having trastuzumab, to now having a wide selection of different agents and different classes, including antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates (ADCs). 

Having this array of different agents has allowed us to provide patients in the metastatic setting with several options for treatment, and survival in the metastatic setting is much longer now than it was 20 years ago. Most importantly, the long-term, invasive disease-free survival rates are very high in early-stage HER2+ breast cancer, even for high-risk patients, through the use of trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1), and, sometimes, neratinib. 

Lastly, because we currently have 8 different US Food and Drug Administration (FDA)–approved drugs targeting HER2 in the clinic, we do have some flexibility in terms of being able to switch therapies in an individual who is not tolerating a particular drug. Patient quality of life has also improved with the FDA approval of a subcutaneous formulation of the combination of trastuzumab and pertuzumab, which decreases administration time so patients do not have to be at the clinic as long. 

I think that changes in the HER2 therapeutic landscape and the impact of clinical outcomes are a model for how advances can be made in cancer in a relatively short time frame by historical standards. The discovery that HER2 overexpression is associated with the worst outcomes in breast cancer was reported in 1987. Within 15 years, we had the FDA approval of the anti-HER2 antibody therapy trastuzumab, which improved outcomes in patients with advanced HER2-overexpressing breast cancer. 

So, with this discovery, we could begin to identify the subset of patients with breast cancer who would benefit from trastuzumab therapy, and that was based on 2 key points. First, identifying a subset of patients whose breast tumors utilized the HER2 pathway enabled clinicians to identify those individuals who would benefit from HER2-directed therapy. It is very possible that trastuzumab may not have shown clinical benefit if it was tested in an unselected group of patients. Second, it was one of the first drugs to provide proof of concept for using a monoclonal antibody to treat cancer. Fast-forward to 2005, which is only approximately 20 years after the initial discovery of HER2, when it was shown that the addition of trastuzumab to chemotherapy in the adjuvant setting could reduce the risk of recurrence by approximately one-half. Further improvements include the availability of dual anti–HER2-directed therapy that targets different domains of the HER2 molecule.

Another advance in the treatment of HER2+ breast cancer was the discovery of tyrosine kinase inhibitors and learning how to use them in combination with antibodies. Additionally, the development of ADCs that can overcome mechanisms of resistance and truly target the tumors that overexpress HER2 is a very important advance. And, taking it a level further, another major advance has been made in the targeting of tumors that have lower levels of HER2 expression but amplification of the gene. 

The field of HER2+ breast cancer has evolved significantly, particularly over the last 2 to 3 years. We initially saw significant advancements with the very first introduction of trastuzumab, where it was shown that adding trastuzumab to chemotherapy dramatically improved outcomes for patients with HER2+ disease. Then came other agents that targeted HER2, such as pertuzumab, which inhibits HER2 dimerization, leading to improvements in survival outcomes for patients with metastatic HER2+ disease, as seen in the phase 3 CLEOPATRA trial. 

Next came the ADCs that are FDA approved for breast cancer. T-DM1 performed better than treatment of physicians' choice in the phase 3 TH3RESA study and better than capecitabine plus lapatinib in the phase 3 EMILIA trial, establishing itself as a second-line metastatic standard. 

We have recently seen an explosion in the number of HER2-directed therapies. For instance, trastuzumab deruxtecan (T-DXd) has now replaced T-DM1 as the second-line standard of care for metastatic HER2+ disease based on data from the DESTINY-Breast03 trial. This phase 3 study showed a landslide in terms of improvements in progression-free and overall survival compared with T-DM1. These large benefits suggest that T-DXd is likely going to have benefits in early lines of therapy and also potentially help us cure more patients with early-stage HER2+ disease in the near future.

The phase 3 KATHERINE trial in early-stage HER2+ breast cancer showed us that we could adapt therapy based on response in the preoperative setting, where we saw that using T-DM1 was better than using trastuzumab in the adjuvant setting for those who failed to achieve a pathological complete response to neoadjuvant HER2-directed therapy. This revolutionized the way we think about treating early-stage HER2+ disease and the critical nature of adapting adjuvant therapy based on response. Planned studies will likely see if T-DXd could replace T-DM1 in this post-preoperative setting in high-risk patients.